The present invention relates to so-called solid reagents (also referred to as polymer-bound reagents or polymer-supported reagents).
Many reagents used in various organic syntheses such as oxidizing agents, reducing agents, deprotonating agents, halogenating agents and nucleophilic displacing agents are hard to handle because of their properties such as toxicity, combustibility, volatility and corrosiveness. They are sometimes poor in the yield or selectivity of target compounds. Moreover, common reagents are mixed with a starting material in a solvent for a desired reaction so that they require complex operations such as extraction, filtration, drying and purification in order to remove unreacted reagents and by-products from the medium and to isolate only a target compound after the reaction, and many of them have the problem that they generate a large volume of waste.
As one of means for solving or reducing these problems, solid reagents have been developed in which a reactive functional group or a reagent compound itself is immobilized on a carrier such as silica gel or a polymer resin.
Polymer resins have found a wide range of applications in chemical syntheses since Merrifield proposed application for peptide synthesis in the 1970s. Among others, many reports proposed using polymer resins as carriers for solid reagents, as introduced in reviews such as Angew. Chem. Int. Ed., 40, 650 (2001), Synthesis, No. 8, 1035 (2000).
The use of solid reagents in organic syntheses generally has the following advantages. They are safer and easier to handle than conventional equivalent reagents (liquid or gaseous reagents); target compounds can be obtained with high yield by excessively using such reagents; and unreacted and reacted reagents and target compounds can be readily separated by filtration after the reaction has been completed. Many of them further have the following advantages. Some kinds of solid reagents afford target compounds with higher selectivity than conventional equivalent reagents; target compounds can be obtained only by passing a solution of a starting compound through a column packed with a solid reagent; and solid reagents can be regenerated/reused. It can be said from these facts that processes using solid reagents are environment-conscious. Solid reagents may be used by passing a solution of a starting compound through a bed of a solid reagent as described above or by passing a gas of a starting compound through a bed of a solid reagent, though the following description is limited to the mode in which a solution is passed for convenience sake. However, solid reagents including those of the present invention naturally cover the application mode in which a raw material gas is passed and such a mode is also included in the scope of the present invention.
Some of these results have already been commercialized. For example, some of ion exchange resins commercially available under Amberlyst have been converted from salt forms to have functions as oxidizing agents, reducing agents, various halogenating agents or nitrating agents. Polymer resins other than ion exchange resins are also commercially available such as polystyrene resins supporting osmium tetraoxide that was previously difficult to handle (from Wako Pure Chemical Industries, Ltd.).
However, all these conventional solid reagents have the problem that they are liable to physical wear/strength reduction during use because they use polymer resins prepared with crosslinkers (crosslinked polymers) as carriers, which change in volume by swelling or contraction.
Moreover, molecules of a starting compound and reactive functional groups or reagent compound molecules supported on a solid reagent must come into thorough contact with each other in order that a chemical reaction may proceed, but conventional solid reagents generally use porous bead-like resins so that molecules of a starting compound must be diffused for access to reactive functional groups or reagent compound molecules supported on the inner surfaces of micropores of the porous resin beads in order that a desired chemical reaction may proceed, which greatly impedes smooth progress of the chemical reaction.
Furthermore, the starting material solution must be passed at an extremely slow flow rate, and therefore over a very long time when conventional solid reagents are to be used in large-scale column reactions. If the flow rate is increased in this case, the starting compound cannot be sufficiently diffused into the interior side of resin beads, which results in an extremely lowered utilization efficiency of reactive functional groups or reagent compound molecules and therefore a decreased yield of the target compound.
The utilization efficiency of reactive functional groups or reagent compound molecules may be increased by reducing the particle diameter of resin beads or further increasing the surface area, but serious pressure loss (differential pressure) in large-scale reactor systems requires considerable strength in reactors or pumps.
For the reasons described above, conventional solid reagents often had further problems associated with regeneration of used reagents, such as lengthy regeneration procedures, need for large amounts of regenerants and low regeneration efficiency.
Consequentially, very few solid reagents are actually used in industrial chemical processes because of the inevitable problem of the poor cost performance for use in industrial chemical processes despite great many proposals of solid reagents as introduced in the review mentioned above.
Several means to solve the above problems were proposed from the aspect of hardware such as reaction vessel or reaction apparatus, but solid reagents optimized for synthetic procedures have been still insufficiently developed.